Treatment of Devic's: comparison study

Mealy MA, Wingerchuk DM, Palace J.  Comparison of relapse and treatment failure rates among patietns with neuromyelitis optica: multicenter study of treatment efficacy.  Jama Neurology 2014; 71:324-330.

 

Retrospective analysis od 90 patients seen over 10 years at Mayo Clinic and JHH treated with azathioprine (n=32), mycophenolate (n=28), and /or rituximab (n=30).

 

Azathioprine reduced the relapse rate 72 % with 53 % failure rate despite concurrent use of prednisone

Mycophenolate reduced relapse rate 87 % with a 36 % failure rate.

Rituximab had an 88 % reduction in relapse rate, with 33 % failure rate.

 

With optimal dosing, rituximab had only a 17 % failure rate.  Ideal dosing was 1000 mg iv, with premedication dose of 100 mg methylprednisolone, with dosage repeated 2 weeks later.  CD 19 was tested monthly, and repeat paired rituximab dosing occurred upon detection of greater than 0.1 % CD19 in total lymphocytes or at regular 6 month intervals.   

 

 

Anti MOG antibody disease

 

Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaphorin-4 and Myelin-oligodendrocyte glycoprotein antibodies: a comparative study.

 

see Levy M. Does aquaphorin-4-seronegative neuromyelitis optica exist? (editorial) JAMA Neurology 2014; 71:271-2.

 

Authors of both studies ferret out a subtype of seronegative NMO that is actually yet another disease.   Anti MOG positve patients with clinical features of NMO have a slightly different phenotype with features of ADEM also.  This group encompasses young males with severe episodes with better recoveries that are more likely to be monophasic, sometimes with simultaneous or rapidly sequential optic neuritis and transverse myelitis.. AntiMOG patients also had more conus involvement on spine MRI and more involvement of deep gray nuclei on brain MRI.  There were no patients with both anti MOG and anti AQU4 antibodies.  anti MOG antibodies are available at Neuroimmunology Testing Service, Oxford, England for 30 pounds).  "n" of the study was 10 aq-4 patients and 9 MOG AB patients. 

 

More clinical information:  4/9 anti MOG and 6/20 AQU$ AB patients had ON as initial invoolvement or part of ; anti MOG had more bilateral ON involvement (75 v. 33 %); both had severe ON when it did happen.  12/20 AQU$ 4 and 9/9 antiMOG had spinal cord involvement initially; Transverse myelitis differed with more bladder involvement in anti MOG patients as iniital symptom (33 v. 0 %) and more late sphincter disturbance in NMO ab patients.  Brain MRI was more likley to be ADEM like in MOG ab patients (44 %) v. 0 % in NMO. 

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NMO mimicking narcolepsy

Patient with presentation of hypersomnolence with diencephalic lesions with presentation of narcolepsy, diagnosed with CSF NMO after negative serum x 3.  Also had low CSF hypocretin levels.

NMO IgG in CSF with negative serum NMO

Klawiter et al.  Neurology 2009; 72:  1101-1102

Authors present 3 cases of NMO with negative serum and positive CSF diagnostic titers of NMO IgG.  Features include absent ON is all cases, rapidly progressive myelitis,

NMO preceded by hyperCKemia episode

Suzuki N et al.  Neurology 2010; 74:1543-1545

3 cases of NMO who had episodes of increased CK with fatigue prior to onset of ON.  Denominator was 733 cases.  Idea is that might represent a prodrome or presentation in those patients.

NMO antibody in CSF but not blood

Klawtizer EC et al. Neurology 2009
Authors have 3 cases of NMO diagnosed by antibody in CSF not blood. All had rapidly relapsing LETM, none had ON although they were followed for less than two years. Authors speculate on role for CSF testing in instances of suspected NMO with negative serum tests.

CNS aquaphorin 4 autoimmunity in children

McKeon A, Lennon VA, Lotze T et al. Neurology 2008; 71:93-100.

Spectrum is such that patients with ON and / pr LETM with positive antibodies are more likely to have recurrence, but also are more likely to have episodic symptoms especially encephalopathy, seizures, nausea, diplopia, vertigo and hiccups. Brain lesions, possibly symptomatic, are seen in 60 % of patients, contrary to prior teaching. 42 % had other coexisting autoimmune diseases including SLE, JRA, Graves, and Sjogren's . More than half had residual disability. 84 % improved with iv methylprednisolone which was usually used as first therapy.

Relationship of PRES and NMOSD

Magana SM, Matiello M, Pittock SJ et al. Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurology 2009; 72:712-717.

Authors introduce NMOSD as inaugural forms of NMO. They note NMOSD and PRES previously have not been related. Authors found five patients with NMOSD who subsequently developed PRES. All patients presented with confusion/impaired consciousness/coma. Patients without clinical NMO with PRES were NMO antibody negative.

Quick hits from the AAN 2008

1. Mycophenolate mofetil (Cellcept) was used to treat 25 patients with NMO and NMO "spectrum" disorders and was effective overall
2. DPB1*0501 allele was represented in Asian NMO but not Caucasian NMO
3. 15 individuals in 7 families were found with familial NMO, a small number suggesting a complex genetic susceptibility
4. Japanese opticospinal MS had 2 groups: one antibody positive and one negative to aquaphorin. The negative group had a marked peripheral Th1 shift.
5. 47 patients (1.3% of MS sample) were found in a study in Turkey
6. Fatigue is less common in NMO than in MS between attacks
7. Four patients with cervical spinal stenosis were misdiagnosed with NMO. They all were antibody negative and did not respond to immune modulation but did to surgery.
8. In 2 Italian patients, celiac disease may have triggered NMO
9. In a Chinese study of NMO patients, brain lesions were common.
10. In Japan, brain lesions developed AFTER starting interferon B1b in NMO in 2 patients.

The spectrum of neuromyelitis optica

Wingerchuk D,Lennon VA, Luchinetti CF, Pittock SJ,Weinshenker BG. Lancet Neurology 2007;6:805-815. Excellent review article from the group at the "WFMC" (World Famous Mayo Clinic).

Asian/African populations

have overrepresentation in NMO cohorts with a small genetic component. Clinically it is slightloy different in Japanese.

NMO IgG

Lennon et al. applied indirect immunofluorescence to mouse CNS tissue and found that 33/45 patients with NMO (73%) were seropositive with no false positives. The target antigen is aquaphorin 4 the dominant water channel in the CNS. It is located on the astrocyte foot processes ("glia limitans") right on the blood brain barrier. Several studies have shown aquaphorin loss in lesions in NMO patients. You get immune complex deposition, necrosis and cavitation that are vasculocentric. Aquaphorin-4 is not lost in MS.

Trigger antigen-- unknown. Binds aquaphorin, activates complement, which together with IL 8 and Il-17 recruit additional inflammatory cells and cause an intense inflammatory necrosis. There is no clonal expansion as antibody circulates in blood and notgenerated in CSF unlike MS. This may explain why NMo responds so well to plasmapheresis.

Transverse myelitis

Kaplin AI et al. The Neurologist. Diagnosis and management of acute myelopathies. 2005; 11:2-18. Review article

Incidence: 1-8 cases per million per year.

Nosology: idiopathic (most) v. associated with a known inflammatory disease (MS, SLE, Sjogren's, NMO, neurosarcoidosis). In the JHTMC only 20 % recurred, 80 % were monophasic. Regional specificity helps the diagnosis eg. cord plus ON is c/w ON, whereas brain involvement suggests ADEM.

Pathology- depends on process, but all have focal monocyrtic infiltration, into perivascular spaces and astroglial and microglial activation. Gray and white matter of cord both are affected and central cord is often affected. Lupus cases may be associated with a CNS vasculitis OR thrombotic infarct of the cord. Sarcoid has noncaseating granulomas whereas MS has perivascular lymphocyte cuffing mononuclear cell infiltration. Postvaccination TM is described with influenza vaccine and booster hepatitis B. Postinfectious causes have numerous and growing numbers of bacteria and viruses associated including Listeria and HSV. Molecular mimicry, analagous to that seen in GBS after Campylobacter infection, is described with Enterobium vermicularis (pinworm) infection. Superantigen mediated infection (eg. Strep B infection with polyclonal expansion of T cells) is postulated.

NMO and recurrent TM involves humoral abnormal immune function that then activate other components of the immune system. It indicates polyclonal derangement of the immune system. It may not be just autoantibodies, but high levels of circulating antobodies that cause recurrent TM. They may form immune complexes. This occurred with hepB sAg. Several Japanese patients had very high IgE levels (360 v. 52 in MS and 85 in normal controls). They had high IgE to household mites (Dermatophagoides farinae) with antibody deposition in the spinal cord, perivascular lymphocyte cuffing and eosinophilic migration. The recruited eosinophils are thought to have induced the neural injury.

In the JHTMC, elevated IL-6 correlated strongly with disability (unlike MS). IL-6 correlated with nitrous oxide that also correlated with disability.

Predictors of recurrence are multifocal lesions in cord or brain, OCB's in CSF, presence of 14,3,3protein

Pathology

Stadelman C, BruckW. Lessons from the neuropathology of atypical forms of multiple sclerosis. NeurolSci. 25: S319-S322 2004

This is an "old" paper since itg describes NMO as "idiopathic." It cites a Brain paper (1999) authored by A Bitsch (that is first initial A, last name.)The lesions are destructive and necrotic with cavitation, acute axonal pathology (spheroids), decreased oligodendrocytes within lesions, many macrophages andgranulocytes and eosinophils. Only sparse CD3+ and CD8+ T lymphocytes are detectable. There was perivascular IGm deposition and the terminal complement component (C9neo antigen) within lesions. There was prominent vascular fibrosis and hyalinization seen. Theyt resemble the antibody-complement mediated pattern of MS suggesting a role for humoral antibodies. Antibody deposition, complement activation and eosinophilic granulocytes suggest a TH2 based immune response.

Hopkins TM Clinic Neurology 68:1615-6 2007

Utilized ASIA a-e scale (a is complete disability and e is normal) for spinal cord as well as EDSS. Authors routinely treat all patients with pulse solumedrol, give some plasmapheresis every other day for five exchanges, pulse cytoxan iv (9750-1000 mg/m2) or combination. "N" for four groups was 66, 32, 13, and 11 respectively in this retrospective review.

Conclusions: 1) Among TM patients without an ASIA A level of disability at nadir or history of AI disease, PLEX provided benefit beyond steroids 2) Among patients with ASIA A presentation, PLEX alone did not help, whereas PLEX plus IV CP helped. 3) if ASIA A was not reached, CP did not add benefit.

Severe recurrent myelitis in hep c

Aktipi et al. Neurology 2007; 68:468-9. Among 59 cases on non MS severe recurrent transverse myelitis were 7 cases with hep C. Only one of the patients knew about hep C at the time of diagnosis. Steroids failed in 4/7. IVIG and alpha interferon were also used. 6 cases had polyradiculoneuritis with enhancement of lumbar roots on MRI. (Italy) NMO antibodies were not looked at.

History of descriptions

The first description was by T. Clifford Allbutt in Lancet . On the opthalmic signs of spinal disease. Lancet. 1870; 1:76-78. However the Frenchman Devic gets credit, even though his protege did the research. Devic E. Myelite subaigue compliquee de nevrite optique. Bull Med 1894;8: 1033-34. Next up was Stansbury FC. Neuromyelitis optica (Devic's disease) Arch Opthalmol 1949; 42:292-335. Beck commented in 1927 on the longitudinally extensive transverse myelitis, cavitation, perivascular infiltration in CNS,

Confirmation of antibody tests

Jarius S et al. NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007;68:1076-77.

NMO IgG was studied in 36 patients with Wingerchuk confirmed clinical criteria for NMO and 80 patients meeting McDonald criteria for MS. 22/36 with NMO and 4/5 with LETM (longitudinally extensive transverse myelitis) had positive antibodies and only one control with MS was positive. Fisher exact test< 0.001. The authors studied a specific pattern of staining in layers of cerebellum including pia and others.

NMO bibliography: recent important papers

Lennon VA; Wingerchuk DM; Kryzer TJ; Pittock SJ; Lucchinetti CF; Fujihara K; Nakashima I; Weinshenker BG. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.Lancet. 2004; 364(9451):2106-2112.

Weinstock-Guttman B; Ramanathan M; Lincoff N; Napoli SQ; Sharma J; Feichter J; Bakshi R. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease).Arch Neurol. 2006; 63(7):957-63.

Pittock SJ; Lennon VA; Krecke K; Wingerchuk DM; Lucchinetti CF; Weinshenker BG. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006; 63(3):390-6.

Correale J; Fiol . Activation of humoral immunity and eosinophils in neuromyelitis optica. Neurology. 2004; 63(12):2363-70

Pittock SJ; Weinshenker BG; Lucchinetti CF; Wingerchuk DM; Corboy JR; Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression.Arch Neurol. 2006; 63(7):964-8 .

Watanabe S; Nakashima I; Misu T; Miyazawa I; Shiga Y; Fujihara K; Itoyama Y. Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica.Mult Scler. 2007; 13(1):128-32.

Wingerchuk DM; Pittock SJ; Lucchinetti CF; Lennon VA; Weinshenker BG. A secondary progressive clinical course is uncommon in neuromyelitis optica.Neurology. 2007; 68(8):603-5

NMO Treatment

Again, NMO typically lacks secondary progression and therapy is designed to address acute attacks and limit destruction thereof. For acute attacks, an initial course of Solumedrol is standard consisting of 5-7 days of treatment. Refractory cases are often highly responsive to plasma exchange. Weinshenker studied exchange v. sham exchange in a group of patients with neurologic disease many of whom had NMO, and 42 % responded. His protocol is seven phereses QOD over 14 days. For attack prevention, standard MS therapies are ineffective. Standard immunosuppression consists of a combination of azathioprine and prednisone. As in other neurologic diseases, azathioprine has a long latency to effect and relapses can occur in the interinm that are prevented with prednisone. Mycophenolate can be substituted for azathioprine, but cannot be titrated based on MCV and WBC making it a blind therapy. Frohmann's IV MTX case used 2.5 gram / meter squared wiuth leukovorin rescue. Rituximab is an anti CD20 MAB that eliminates pre B and mature B cells. 4 weekly infusions each involving 375 mg/m(2); 7/8 had had breakthrough disease and 6/8 remained relapse free with an EDSS improvement from mean 7.5 to 5.5. After B Cell recovery 2 more infusions of 1000 mg 2 weeks apart are given. Mmitoxantrone is also an option. The protocol in theonly study done was changed to give more MTX upfront, due to patients relapsing early if every 3 month therapy was chosen. IVIG stabilized 2 patients with active disease despite azathioprine and steroid therapy

More clinical information about NMO

In Cree's summary of NMO in Seminars in Neurology, women predominated by 2.3:1, the mean age of onset was 37, 45 % presented with ON, 38 % with myelitis, 17 % with both, 76 % had a normal brain MRI, more than half had a CSF pleocytosis, and had PMN's in the CSF . The ratio of polyphasic to monophasic disease was 1.8 : 1. Although the prognosis was poor , there were benign cases. Galetta stressed that although LETM (Long extensive transverse myelitis) was characteristic, skip areas also occurred in the cord.

Although the brain lesions were unique according to the Mayo article, a certain percentage has ovoid or periventricular lesions indistinguishable from MS. In patients with NMO with transverse myelitis, recurrence was more common (vice versa). Hiccups and nausea imply a medullary lesion and occur in 17 %. NMO is positive from the very earliest stage. Rarely, patients are NMO negative or have antibodies to another antigen such as MUSK. The complement mediation of destruction is characteristic.

A spectrum of disease probably exists including idiopathic recurrent isolated LETM, recurrent ON with a negative brain MRI, and Asian optic-spinal MS. Standard MS therapies are not effective but specific NMO therapies can be not only effective but occassionally dramatically so in seemingly hopeless cases. Elliott Frohmann described a patient who was limited to movement of one finger, who was treated with high dose IV methotrexate, and recovered completely including driving, living independently, raising her children.

More on NMO Pathology and Aquaphorin story

100 percent of the lesions in NMO are perivascular around the microvessels. The perivascular staining to C9neo is far greater than in multiple sclerosis. Rosettes form. The specific antigen is aqp4 which is a membrane protein involved in water transport in NMO. AQP4 co-localizes with the NMO IgG precipitate . Staining is in pial, not endothelial and was described by Lennon and Weinshenker. AQP4 is not localized elsewhere in CNS but has been localized in crypts in gastric mucosa and distal renal tubules.

Is NMO different than a form of MS? No, but..

The following is based on presentations at a conference including Elliott Frohmann, Brian Weinshenker, Stephen Galetta and others. Officially, it is not yet established as a different disease, but is different based on demographic, clinical, MRI, pathological, immunologic, prognostic, and therapeutic criteria.

Clinical differences between NMO and MS abound. The spinal cord lesions in the two diseases are different. In NMO, the lesions are in the central gray, extend over many segments, and may be necrotic. Eosinophils and neutrophils are abundant. The inflammation is extensive in perivascular areas especially in the micro-vessels. In MS, spinal cord lesions are non-necrotic, smaller, macrophages predominate, and inflammation occurs at the edge of the plaque and along myelin sheaths, not nearly as much along the perivascular edges. Unlike NMO, rosettes do not form.

In NMO, oligoclonal banding is absent, unlike MS. Clonal expansion is not important in NMO, suggesting that the blood brain barrier is not integral to the process. NMO IgG is present in 70 % of cases, v. < 10 % in MS. Systemic autoimmune disease suchas Sjogren's and lupus are abundant, whereas there is only a slight increase in autoimmunity in MS. Many cases of myelitis in patients with SLE or Sjogren's previously thought to be vasculitis are NMO positive, suggesting a different diagnosis. Recurrent transverse myelitis is often NMO positive, suggesting a subset of patients with that condition have that diagnosis. In MRI, brain lesions are "uncommon" in NMO but can occur. They usually are located around the hypothalamus, thalamus and third ventricle, and around the periphery of the cerebellum. However, 8% or so are atypical and can mimic the lesions in multiple sclerosis, with hemispheric lesions. Brain lesions, like cord lesions, can present as long linear lesions in the medulla especially in area postrema and the solitary tract. In one series, 17 %of patients presented with hiccups, correalting with the above pathology. Similarly, optic nerve lesions may be long and centrally located in NMO and extend all the way back to the chiasm. CSF often has a pleocytosis. Asian demyelinating variants may in some cases represent NMO.

Unlike MS, in NMO a secondary progressive course is rare and damage is done during the attacks themselves. If the attacks can be controlled, so can the disease. Plasmapheresis works extremely well in this condition.Rituxan works well as a chronic treatment to control attacks. Beta interferon does not work well.

Diagnostic Criteria-- Wingerchuk criteria

Neurology 2006

* Clinical events involving optic nerve(s) and spinal cord and (2) of (3) of following
* Long extensive spinal cord lesions (> 3 segments common)
* Brain MRI normal or not meeting criteria for multiple sclerosis
* NMO IgG seropositive status